It is known that BAFF (B cell activating factor belonging to the TNF family) is produced and secreted from T cells, monocytes/macrophages, dendritic cells and the like and regulates such as B-cell differentiation, activation, survival rate via 3 types of receptors on B cells (Moore et al., Science, 285, 260-263 (1999)).
Human BAFF is a transmembrane form protein comprising 285 amino acids. There is a structural characteristic of trimer formation such as the presence of a cytoplasmic domain of 46 amino acids, an extracellular domain of 218 amino acids, and two N-glycosylation sites in its amino acid sequence. It is estimated that an extracellular domain of 152 amino acids from C-terminal is cleaved with a protease of Furin family and released in a soluble form. The amino acid sequence of human BAFF initially named neutrokine α was disclosed as SEQ ID NO: 1 or 2 in publication of International Patent Application WO98/18921. Other names of human BAFF such as Kay, TNFSF13B, Blys, TALL-1, THANK and zTNF4 are also known.
BAFF-R, TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor), and BCMA (B cell maturation antigen) are known as BAFF receptors. BAFF-R and BCMA are expressed mainly in B cells, and TACI is expressed in B cells and activated T cells.
The physiological action of BAFF lies in regulation of B-cell differentiation, activation, survival rate and the like as described above, and is increasingly revealed in recent years to participate in pathologic condition. That is, it is reported that a mouse expressing BAFF in excess shows SLE-like symptoms such as increase in peripheral blood B cells, enlargement of lymph nodes and spleen, increase in IgG level in serum, antinuclear antibody production, deposition of immune complex in the kidney, albuminuria and nephritis (Mackay et al., J. Exp. Med., 190, 1697-1710, (1999), and Khare et al., Proc. Natl. Acad. Sci. USA 97, 3370-3375, (2000)). It was further reveled that this mouse also shows SS-like symptoms such as inflammation of salivary gland and destruction of salivary gland with advancing age (Groom et al., J. Clin. Invest., 109, 59-68, (2002)) An increase of BAFF level in serum in patients suffering from SLE, RA and SS is also reported (Zhanget al., J. Immunol., 166, 6-10, (2001); Cheema et al., Arthritis Rheum., 44, 1313-1319, (2001); and Groom et al., J. Clin. Invest., 109, 59-68, (2002)), and there are also many reports such as higher BAFF level in synovial fluid than in serum in patients suffering from RA (Cheema et al., Arthritis Rheum., 44, 1313-1319, (2001)), expression of BAFF in salivary gland-infiltrating leukocytes in patients suffering from SS (Groom et al., J. Clin. Invest. 109, 59-68, (2002)), correlation between serum BAFF level in patients suffering from SLE and immunoglobulin or anti-ds DNA antibody (Zhang et al., J. Immunol. 166, 6-10, (2001)) and correlation between BAFF in patients suffering from RA and rheumatoid factor (Cheema et al., Arthritis Rheum., 44, 1313-1319, (2001)).
From these facts, it can be said that the suppression or inhibition of expression or production of BAFF leads to prevention and treatment of autoimmune diseases such as SLE, RA and SS, and thus there is demand for establishment of a system for accurately screening the suppression or inhibition of expression or production of BAFF.
For establishment of such screening system, it is possible to anticipate, for example, a method of obtaining a cell expressing BAFF stably by transforming a cultured cell with a gene vector constructed so as to express BAFF by recombinant DNA techniques. There is however a problem that even if BAFF could be expressed, BAFF would not always released extracellularly in a secretory form and would be uncertain as to whether the cultured cell can be a cell strain stable for expression and production of BAFF. Accordingly, none of such system has been reported. For example, if it would be possible to construct a system wherein the induction of intracellular expression of BAFF and the extracellular release of a detectable sufficient amount of BAFF can be recognized when a commercial cell strain is subjected to suitable stimulating conditions, the problem described above could be solved.